A 2D ferroelectric vortex pattern in twisted BaTiO3 freestanding layers.

The wealth of complex polar topologies1-10 recently found in nanoscale ferroelectrics results from a delicate balance between the intrinsic tendency of the materials to develop a homogeneous polarization and the electric and mechanical boundary conditions imposed on them. Ferroelectric-dielectric interfaces are model systems in which polarization curling originates from open circuit-like electric boundary conditions, to avoid the build-up of polarization charges through the formation of flux-closure11-14 domains that evolve into vortex-like structures at the nanoscale15-17 level. Although ferroelectricity is known to couple strongly with strain (both homogeneous18 and inhomogeneous19,20), the effect of mechanical constraints21 on thin-film nanoscale ferroelectrics has been comparatively less explored because of the relative paucity of strain patterns that can be implemented experimentally. Here we show that the stacking of freestanding ferroelectric perovskite layers with controlled twist angles provides an opportunity to tailor these topological nanostructures in a way determined by the lateral strain modulation associated with the twisting. Furthermore, we find that a peculiar pattern of polarization vortices and antivortices emerges from the flexoelectric coupling of polarization to strain gradients. This finding provides opportunities to create two-dimensional high-density vortex crystals that would enable us to explore previously unknown physical effects and functionalities.

Disentangling Photodoping, Photoconductivity, and Photosuperconductivity in the Cuprates.

The normal-state conductivity and superconducting critical temperature of oxygen-deficient YBa_{2}Cu_{3}O_{7-δ} can be persistently enhanced by illumination. Strongly debated for years, the origin of those effects-termed persistent photoconductivity and photosuperconductivity (PPS)-has remained an unsolved critical problem, whose comprehension may provide key insights to harness the origin of high-temperature superconductivity itself. Here, we make essential steps toward understanding PPS. While the models proposed so far assume that it is caused by a carrier-density increase (photodoping) observed concomitantly, our experiments contradict such conventional belief: we demonstrate that it is instead linked to a photo-induced decrease of the electronic scattering rate. Furthermore, we find that the latter effect and photodoping are completely disconnected and originate from different microscopic mechanisms, since they present different wavelength and oxygen-content dependences as well as strikingly different relaxation dynamics. Besides helping disentangle photodoping, persistent photoconductivity, and PPS, our results provide new evidence for the intimate relation between critical temperature and scattering rate, a key ingredient in modern theories on high-temperature superconductivity.

Extremely long-range, high-temperature Josephson coupling across a half-metallic ferromagnet.

The Josephson effect results from the coupling of two superconductors across a spacer such as an insulator, a normal metal or a ferromagnet to yield a phase coherent quantum state. However, in junctions with ferromagnetic spacers, very long-range Josephson effects have remained elusive. Here we demonstrate extremely long-range (micrometric) high-temperature (tens of kelvins) Josephson coupling across the half-metallic manganite La0.7Sr0.3MnO3 combined with the superconducting cuprate YBa2Cu3O7. These planar junctions, in addition to large critical currents, display the hallmarks of Josephson physics, such as critical current oscillations driven by magnetic flux quantization and quantum phase locking effects under microwave excitation (Shapiro steps). The latter display an anomalous doubling of the Josephson frequency predicted by several theories. In addition to its fundamental interest, the marriage between high-temperature, dissipationless quantum coherent transport and full spin polarization brings opportunities for the practical realization of superconducting spintronics, and opens new perspectives for quantum computing.

Controlled Sign Reversal of Electroresistance in Oxide Tunnel Junctions by Electrochemical-Ferroelectric Coupling.

The persistence of ferroelectricity in ultrathin layers relies critically on screening or compensation of polarization charges which otherwise destabilize the ferroelectric state. At surfaces, charged defects play a crucial role in the screening mechanism triggering novel mixed electrochemical-ferroelectric states. At interfaces, however, the coupling between ferroelectric and electrochemical states has remained unexplored. Here, we make use of the dynamic formation of the oxygen vacancy profile in the nanometer-thick barrier of a ferroelectric tunnel junction to demonstrate the interplay between electrochemical and ferroelectric degrees of freedom at an oxide interface. We fabricate ferroelectric tunnel junctions with a La_{0.7}Sr_{0.3}MnO_{3} bottom electrode and BaTiO_{3} ferroelectric barrier. We use poling strategies to promote the generation and transport of oxygen vacancies at the metallic top electrode. Generated oxygen vacancies control the stability of the ferroelectric polarization and modify its coercive fields. The ferroelectric polarization, in turn, controls the ionization of oxygen vacancies well above the limits of thermodynamic equilibrium, triggering the build up of a Schottky barrier at the interface which can be turned on and off with ferroelectric switching. This interplay between electronic and electrochemical degrees of freedom yields very large values of the electroresistance (more than 10^{6}% at low temperatures) and enables a controlled switching between clockwise and counterclockwise switching modes in the same junction (and consequently, a change of the sign of the electroresistance). The strong coupling found between electrochemical and electronic degrees of freedom sheds light on the growing debate between resistive and ferroelectric switching in ferroelectric tunnel junctions, and moreover, can be the source of novel concepts in memory devices and neuromorphic computing.

Ferroelectric Control of Interface Spin Filtering in Multiferroic Tunnel Junctions.

The electronic reconstruction occurring at oxide interfaces may be the source of interesting device concepts for future oxide electronics. Among oxide devices, multiferroic tunnel junctions are being actively investigated as they offer the possibility to modulate the junction current by independently controlling the switching of the magnetization of the electrodes and of the ferroelectric polarization of the barrier. In this Letter, we show that the spin reconstruction at the interfaces of a La_{0.7}Sr_{0.3}MnO_{3}/BaTiO_{3}/La_{0.7}Sr_{0.3}MnO_{3} multiferroic tunnel junction is the origin of a spin filtering functionality that can be turned on and off by reversing the ferroelectric polarization. The ferroelectrically controlled interface spin filter enables a giant electrical modulation of the tunneling magnetoresistance between values of 10% and 1000%, which could inspire device concepts in oxides-based low dissipation spintronics.

Therapeutic antidepressant potential of a conjugated siRNA silencing the serotonin transporter after intranasal administration.

Major depression brings about a heavy socio-economic burden worldwide due to its high prevalence and the low efficacy of antidepressant drugs, mostly inhibiting the serotonin transporter (SERT). As a result, ~80% of patients show recurrent or chronic depression, resulting in a poor quality of life and increased suicide risk. RNA interference (RNAi) strategies have been preliminarily used to evoke antidepressant-like responses in experimental animals. However, the main limitation for the medical use of RNAi is the extreme difficulty to deliver oligonucleotides to selected neurons/systems in the mammalian brain. Here we show that the intranasal administration of a sertraline-conjugated small interfering RNA (C-SERT-siRNA) silenced SERT expression/function and evoked fast antidepressant-like responses in mice. After crossing the permeable olfactory epithelium, the sertraline-conjugated-siRNA was internalized and transported to serotonin cell bodies by deep Rab-7-associated endomembrane vesicles. Seven-day C-SERT-siRNA evoked similar or more marked responses than 28-day fluoxetine treatment. Hence, C-SERT-siRNA (i) downregulated 5-HT1A-autoreceptors and facilitated forebrain serotonin neurotransmission, (ii) accelerated the proliferation of neuronal precursors and (iii) increased hippocampal complexity and plasticity. Further, short-term C-SERT-siRNA reversed depressive-like behaviors in corticosterone-treated mice. The present results show the feasibility of evoking antidepressant-like responses by selectively targeting neuronal populations with appropriate siRNA strategies, opening a way for further translational studies.

Emergent spin filter at the interface between ferromagnetic and insulating layered oxides.

We report a strong effect of interface-induced magnetization on the transport properties of magnetic tunnel junctions consisting of ferromagnetic manganite La0.7Ca0.3MnO3 and insulating cuprate PrBa2Cu3O7. Contrary to the typically observed steady increase of the tunnel magnetoresistance with decreasing temperature, this system exhibits a sudden anomalous decrease at low temperatures. Interestingly, this anomalous behavior can be attributed to the competition between the positive spin polarization of the manganite contacts and the negative spin-filter effect from the interface-induced Cu magnetization.

Genetic variations of patients with familial or multiple melanoma in Southern Brazil.

BACKGROUND: Patients with familial melanoma or multiple primary melanoma represent a high-risk population to hereditary melanoma. Mutations in susceptibility genes, such as CDKN2A, CDK4 and MC1R, have been associated with the development of melanoma. OBJECTIVES: The purpose of this study was to determine the genotypic background of patients with familial and/or multiple melanoma in southern Brazil. METHODS: This study analysed 33 cases (5 patients with multiple primary melanoma and 28 patients from families with at least two well documented cases) and 29 controls. Genomic analysis of CDKN2A and CDK4 genes by PCR-SSCP analysis and sequencing and direct sequencing of MC1R were performed in all individuals. RESULTS: No functional mutations in CDKN2A or CDK4 were detected in the 62 individuals. Infrequent variants in polymorphic loci of CDKN2A gene were identified in 15 participants (24.2%) and 24/33 (72.8%) cases and 19/27 (70.4%) controls reported at least one infrequent variant in MC1R (P = 0.372). Furthermore, a non-significant tendency towards an association between melanoma risk and MC1R variants G274A and C451T and a non-significant linear tendency to the number of infrequent high-risk variants in MC1R were observed. CONCLUSIONS: These results suggest that in southern Brazilian population, CDKN2A or CDK4 germinal alterations may have a weaker influence than previously thought and environmental risk factors may play a central role in melanoma susceptibility. However, considering the tendency observed for gene MC1R, low-penetrance genes may be a relevant aetiological factor in southern Brazil with fair skin population and high sunlight exposure.

Dermoscopic features of melanomas associated with MC1R variants in Spanish CDKN2A mutation carriers.

BACKGROUND: The presence of at least one MC1R gene variant is associated with a reduction in age at melanoma diagnosis in families with CDKN2A mutations. OBJECTIVES: To describe dermoscopic features of early melanoma in CDKN2A gene mutation-positive Spanish individuals and to evaluate the possibility of a correlation between particular dermatoscopic pattern and MC1R gene variants. METHODS: Patients in whom a melanoma was diagnosed during specific follow up of high-risk individuals carrying CDKN2A mutations (with familial or personal history of previous melanoma) were included in this study. The decision to remove such melanomas was taken on the basis of history, clinical and dermoscopic evaluations including total body photography and digital dermoscopy. RESULTS: Of the nine patients included in this study, three were noncarriers of the red hair MC1R polymorphism, three patients had one red hair MC1R polymorphism and three patients had two red hair MC1R polymorphisms. On dermoscopic analysis of suspect melanocytic lesions we found that the mean +/- SD ABCD total dermoscopy score (TDS) was significantly higher in noncarriers of red hair MC1R polymorphisms than in carriers of two MC1R gene red hair variants (6.8 +/- 0.4 vs. 4.4 +/- 0.9; P = 0.014). CONCLUSIONS: Early melanomas in patients with two MC1R red hair variants may be difficult to diagnose definitively by dermoscopy because, in our limited experience, they show fewer colours and structures and have a lower TDS. In such melanomas, subtle atypical vessels and other changes detected by digital image follow up may be useful to confirm the diagnosis of melanoma. An integrated approach including clinical history and dermoscopic data (also considering additional information, such as the presence of atypical vessels) should be utilized in evaluating these high-risk patients. Further studies are necessary to confirm our suggestion.

CDKN2A mutations in melanoma families from Uruguay.

BACKGROUND: Familial melanoma, a cluster of several cases within a single family, accounts for approximately 10% of cases of melanoma. Hereditary melanoma is defined as two or more first-degree relatives having melanoma. A member of a melanoma-prone family has a 35-70-fold increased relative risk of developing a melanoma. Genetic susceptibility is linked to the major susceptibility genes CDKN2A and CDK4, and the minor susceptibility gene MC1R. OBJECTIVES: To determine the clinical and genetic characteristics of cutaneous melanoma in melanoma-prone families from Uruguay. METHODS: We studied 13 individuals from six melanoma-prone families living in Uruguay. Phenotype, familial and personal history were recorded. Molecular screening of CDKN2A and CDK4 was done by polymerase chain reaction-single strand conformational polymorphism analysis. The MC1R gene was sequenced. RESULTS: Mutations in CDKN2A were detected in five of six families: c.-34G>T, p.G101W and p.E88X. A novel germline mutation p.E88X, associated with hereditary melanoma in two unrelated families, is described. We hypothesize that a founder effect occurred probably in the Mediterranean region. No mutations in CDK4 were detected. Six different MC1R variants, all previously reported, were present in Uruguayan families. CONCLUSIONS: The overall rate of deleterious CDKN2A mutations in our familial melanoma pedigrees, even though the sample size is small, was considerably higher (83%) than the often quoted range.

Pharmacological characterization and autoradiographic distribution of alpha2-adrenoceptor antagonist [3H]RX 821002 binding sites in the chicken brain.

Knowledge about the noradrenergic system in birds is very scarce even though their biological diversity and complex social behavior make them an excellent model for studying neuronal functions and developmental biology. While the role of norepinephrine has been described in depth in a large number of central and peripheral functions in mammals, reports for avian species are limited. The radioligand [(3)H]RX 821002 ([(3)H]1,4-[6,7(n)3H]-benzodioxan-2-methoxy-2-yl)-2-imidazol) has been used to map and characterize alpha(2)-adrenoceptors through the chicken brain using in vitro autoradiography and membrane homogenates binding assays. [(3)H]RX 821002 showed a saturable and high affinity binding to a site compatible with alpha(2)-adrenoceptor, and to a serotonergic component. The autoradiographic assays displayed a similar alpha(2)-adrenoceptor distribution than those previously reported in birds using other radioligands such as [(3)H]UK 14304 ([(3)H]5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine) or [(3)H]clonidine. [(3)H]RX 821002 binding pharmacological characterization was carried out in different chicken brain regions using membrane homogenates for competition assays with different alpha(2)-adrenoceptor agonists and antagonists drugs (oxymetazoline, BRL 44408 [2-(2H-(1-methyl-1,3-dihydroisoindole)methyl)-4,5-dihydroimidazole] ARC 239 [2-(2-4-(O-methoxyphenyl)-piperazin-1-yl)-ethyl-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione], prazosin, UK 14304 and RX 821002). The results showed alpha(2A) as the predominant alpha(2)-adrenoceptor subtype in the chicken brain while alpha(2B)- and/or alpha(2C)-adrenoceptor subtypes were detected only in the telencephalon. RX 821002, serotonin (5-HT) and 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] competition assays, and competition binding assays performed in the presence of serotonin demonstrated that [(3)H]RX 821002 binds with higher affinity to a serotonergic component, probably 5-HT(1A) receptors, than to the alpha(2)-adrenoceptors. Similar pharmacological properties for the alpha(2)-adrenoceptor component were observed both in rat and chicken brain. The results demonstrate that the different alpha(2)-adrenoceptor subtypes are present in chicken brain and suggest that these receptors are highly conserved through evolution.

Cannabinoid system in the budgerigar brain.

Cannabinoid receptor density and cannabinoid receptor-mediated G protein stimulation were studied by autoradiographic techniques throughout the budgerigar (Melopsittacus undulatus) brain. The maximal CB(1) receptor density value (using [(3)H]CP55,940 as radioligand) was found in the molecular layer of the cerebellum (Mol), and high binding values were observed in the nucleus taeniae amygdalae (TnA), nucleus preopticus medialis, and nucleus pretectalis. The highest net-stimulated [(35)S]GTPgammaS binding values induced by the selective CB(1) receptor agonist WIN55,212-2 were observed in the nucleus paramedianus internus thalami, and high values of [(35)S]GTPgammaS binding were observed in the TnA, Mol, arcopallium dorsale and arcopallium intermedium. The distribution data suggest that in the budgerigar, as previously indicated in mammals, cannabinoid receptors may be related to the control of several brain functions in the motor system, memory, visual system, and reproductive behavior. The discrepancies between the cannabinoid receptor densities and the cannabinoid receptor-mediated stimulation found in several budgerigar brain nuclei support the hypothesis, previously described for mammals, of the existence of different G(i/o) protein populations able to associate with the cannabinoid receptors, depending on the brain structure, and could reflect the relative importance that cannabinoid transmission could exerts in each cerebral area.

The absence of 5-HT4 receptors modulates depression- and anxiety-like responses and influences the response of fluoxetine in olfactory bulbectomised mice: Adaptive changes in hippocampal neuroplasticity markers and 5-HT1A autoreceptor.

Preclinical studies support a critical role of 5-HT4 receptors (5-HT4Rs) in depression and anxiety, but their influence in depression- and anxiety-like behaviours and the effects of antidepressants remain partly unknown. We evaluated 5-HT4R knockout (KO) mice in different anxiety and depression paradigms and mRNA expression of some neuroplasticity markers (BDNF, trkB and Arc) and the functionality of 5-HT1AR. Moreover, the implication of 5-HT4Rs in the behavioural and molecular effects of chronically administered fluoxetine was assessed in naïve and olfactory bulbectomized mice (OBX) of both genotypes. 5-HT4R KO mice displayed few specific behavioural impairments including reduced central activity in the open-field (anxiety), and decreased sucrose consumption and nesting behaviour (anhedonia). In these mice, we measured increased levels of BDNF and Arc mRNA and reduced levels of trkB mRNA in the hippocampus, and a desensitization of 5-HT1A autoreceptors. Chronic administration of fluoxetine elicited similar behavioural effects in WT and 5-HT4R KO mice on anxiety-and depression-related tests. Following OBX, locomotor hyperactivity and anxiety were similar in both genotypes. Interestingly, chronic fluoxetine failed to reverse this OBX-induced syndrome in 5-HT4R KO mice, a response associated with differential effects in hippocampal neuroplasticity biomarkers. Fluoxetine reduced hippocampal Arc and BDNF mRNA expressions in WT but not 5-HT4R KO mice subjected to OBX. These results demonstrate that the absence of 5-HT4Rs triggers adaptive changes that could maintain emotional states, and that the behavioural and molecular effects of fluoxetine under pathological depression appear to be critically dependent on 5-HT4Rs.

Hipertrofia maseterina unilateral idiopática / Idiopathic unilateral masseteric hypetrophy

Paciente de 20 años que presentó aumento de volumen facial izquierdo. Estudiado con ecografía, TAC y biopsia quirúrgica. Se establece el diagnóstico de hipertrofia maseterina unilateral idiopática. La hipertrofia maseterina es un desorden benigno que puede manifestarse de forma unilateral o bilateral, que provoca una asimetría facial, frecuentemente asintomática. Se han propuesto varios tratamientos, siendo la infiltración con toxina botulínica tipo A un tratamiento mínimamente invasivo y eficaz

A 20-year-old patient who present an increase in left facial side. Studied with ultrasound, CT scan and surgical biopsy. The diagnosis of idiopathic unilateral masseter hypertrophy was established. Masseter hypertrophy is a benign disorder that can manifest unilaterally or bilaterally, causing facial asymmetry, often asymptomatic. Several treatments have been introduced, such as infiltration with Botulinum toxin type A, a minimally invasive and effective treatment

Bromocriptine mesylate (Parlodel) in the management of amenorrhea/galactorrhea associated with hyperprolactinemia.

The efficacy and safety of bromocriptine mesylate (5 to 7.5 mg per day for up to 24 weeks) were studied in 22 clinical trials involving 226 patients who had amenorrhea/galactorrhea associated with hyperprolactinemia and no demonstrable pituitary tumor. Of the 187 patients evaluated for efficacy, 80% experienced reinitiation of menses (or pregnancy without first having menses); the average treatment time (excluding those who conceived) was 5.7 weeks. Galactorrhea was significantly (at least 75%) reduced in 76% of the 187 patients after an average treatment tome of 6.4 weeks, and was completely suppressed in 58% after 12.7 weeks. Maximum reduction in serum prolactin levels occurred within the first 4 weeks of therapy and the reduced levels were maintained during treatment; moreover, there was a strong correlation between prolactin reduction and clinical improvement. Adverse reactions were reported by 68% of the 226 patients evaluated for safety; in general, these reactions were mild and transient. Several patients experienced hypotension, but only 1 discontinued therapy because of it. Based on these findings, bromocriptine mesylate was judged safe and efficacious for this purpose.

Concertina effect and facial aging: nonlinear aspects of youthfulness and skeletal remodeling, and why, perhaps, infants have jowls.

The effect of aging on the orbitomaxillary region is evaluated in the present study. The observation was made that infants look like aged individuals in terms of the midface soft-tissue contours of the midface. Because preliminary work has shown that the facial skeleton remodels throughout life, this observation led to the hypothesis that infants and older individuals appear similar because they have comparable skeletal dimensions, specifically in the orbitomaxillary region. The design is a retrospective analysis of three-dimensional computed tomographic scan data. Three groups of male subjects were studied: infant, ages 1 to 12 months (n = 5); youthful, ages 15 to 24 years (n = 13); and old, ages 53 to 76 years (n = 12). Orbital and zygomaticomaxillary vertical dimensions were measured in both medial and lateral planes between fixed anatomical landmarks. Results were compared by using analysis of variance, Student-Newman-Keuls, and Student's t tests. The findings show that skeletal remodeling is such that the ratio of the maxillary height to orbital height is greatest during youth; during infancy and old age, there is a short maxilla relative to a larger orbit. This finding is significant in the medial plane from orbital rim to pyriform aperture (p < 0.05). Furthermore, there is an actual decrease in vertical maxillary height in this medial plane (p < 0.01) from youth until old age, which occurs secondary to normal skeletal remodeling in the dentate individual. The combined effect of downward expansion of the orbital shelf and the upward migration of the pyriform effectively decreases the space available to support the overlying soft tissues of the midface. An accordion-like or "concertina" effect may lead to compression or restriction of the facial soft tissues over a relatively deficient bony platform. These results highlight the importance of skeletal remodeling in determining the soft-tissue contours of the aging face. The process of skeletal remodeling may also allow for a tentative definition of facial youthfulness. Infants are born with a short maxilla relative to a large orbit, and the maxillary wall is angled posteriorly. This ratio and angle change from infancy until youth, when there is a balance between the bony skeletal support and the overlying soft-tissue envelope, i.e., the skin, facial muscles, and adipose tissue. It is when skeletal remodeling continues past this point that a disharmony occurs. Because the ratio of maxilla/orbit, and the angle of the maxillary wall, in the older person reverts toward that of an infant, the attainment of youth occurs partly in a nonlinear or multimodal manner. This work is part of an emerging concept of facial aging, which we would term an integrated model of facial aging. This model allows facial aging to be viewed as a biological "system," in which there are primary and secondary factors that interact in the process of facial aging. Additional research such as this continues to suggest the importance of bony remodeling in facial aging.

Reversible electric-field control of magnetization at oxide interfaces.

Electric-field control of magnetism has remained a major challenge which would greatly impact data storage technology. Although progress in this direction has been recently achieved, reversible magnetization switching by an electric field requires the assistance of a bias magnetic field. Here we take advantage of the novel electronic phenomena emerging at interfaces between correlated oxides and demonstrate reversible, voltage-driven magnetization switching without magnetic field. Sandwiching a non-superconducting cuprate between two manganese oxide layers, we find a novel form of magnetoelectric coupling arising from the orbital reconstruction at the interface between interfacial Mn spins and localized states in the CuO2 planes. This results in a ferromagnetic coupling between the manganite layers that can be controlled by a voltage. Consequently, magnetic tunnel junctions can be electrically toggled between two magnetization states, and the corresponding spin-dependent resistance states, in the absence of a magnetic field.

Characterization of surface metallic states in SrTiO3 by means of aberration corrected electron microscopy.

An unusual conducting surface state can be produced in SrTiO3 substrates by irradiation with Argon ions from a plasma source, at low energy and high doses. The effects of irradiation are analyzed here by atomic force microscopy (AFM) and aberration corrected scanning transmission electron microscopy (STEM) combined with electron energy loss spectroscopy (EELS). Depth sensitive studies demonstrate the existence of a heavily damaged surface layer and an oxygen vacancy rich layer immediately underneath, both induced during the irradiation process. We find a clear dependence of the Ti oxidation state with the depth, with a very intense Ti(3+) component near the surface. Oxygen vacancies act as n-type doping by releasing electrons into the lattice and producing an insulator-to-metal transition, which explains the unusual metallic behavior of these samples.

RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis.

Current antidepressants, which inhibit the serotonin transporter (SERT), display limited efficacy and slow onset of action. Here, we show that partial reduction of SERT expression by small interference RNA (SERT-siRNA) decreased immobility in the tail suspension test, displaying an antidepressant potential. Moreover, short-term SERT-siRNA treatment modified mouse brain variables considered to be key markers of antidepressant action: reduced expression and function of 5-HT(1A)-autoreceptors, elevated extracellular serotonin in forebrain and increased neurogenesis and expression of plasticity-related genes (BDNF, VEGF, Arc) in hippocampus. Remarkably, these effects occurred much earlier and were of greater magnitude than those evoked by long-term fluoxetine treatment. These findings highlight the critical role of SERT in serotonergic function and show that the reduction of SERT expression regulates serotonergic neurotransmission more potently than pharmacological blockade of SERT. The use of siRNA-targeting genes in serotonin neurons (SERT, 5-HT(1A)-autoreceptor) may be a novel therapeutic strategy to develop fast-acting antidepressants.

Subchronic treatment with fluoxetine and ketanserin increases hippocampal brain-derived neurotrophic factor, ß-catenin and antidepressant-like effects.

BACKGROUND AND PURPOSE: 5-HT(2A) receptor antagonists improve antidepressant responses when added to 5-HT-selective reuptake inhibitors (SSRIs) or tricyclic antidepressants. Here, we have studied the involvement of neuroplasticity pathways and/or the 5-hydroxytryptaminergic system in the antidepressant-like effect of this combined treatment, given subchronically. EXPERIMENTAL APPROACH: Expression of brain-derived neurotrophic factor (BDNF) and its receptor (TrkB), 5-bromo-2'-deoxyuridine (BrdU) incorporation, and ß-catenin protein expression in different cellular fractions, as well as 5-HT(1A) receptor function were measured in the hippocampus of rats treated with fluoxetine, ketanserin and fluoxetine + ketanserin for 7 days, followed by a forced swimming test (FST) to analyse antidepressant efficacy. KEY RESULTS: mRNA for BDNF was increased in the CA3 field and dentate gyrus of the hippocampus by combined treatment with fluoxetine + ketanserin. Expression of ß-catenin was increased in total hippocampal homogenate and in the membrane fraction, but unchanged in the nuclear fraction after combined treatment with fluoxetine + ketanserin. These effects were paralleled by a decreased immobility time in the FST. There were no changes in BrdU incorporation, TrkB expression and 5-HT(1A) receptor function in any of the groups studied. CONCLUSIONS AND IMPLICATIONS: The antidepressant-like effect induced by subchronic co-treatment with a SSRI and a 5-HT(2A) receptor antagonist may mainly be because of modifications in hippocampal neuroplasticity (BDNF and membrane-associated ß-catenin), without a significant role for other mechanisms involved in chronic antidepressant response, such as hippocampal neuroproliferation or 5-HT(1A) receptor desensitization in the dorsal raphe nucleus.